Characterization of altered immunity in patients with inflammatory arthritis induced by immune checkpoint inhibitor therapy

免疫检查点抑制剂治疗引起的炎症性关节炎患者免疫改变的特征

• 批准号: 10457396
• 负责人: Sang Taek Kim
• 金额: $ 17.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457396
• 关键词: Address; Advanced Malignant Neoplasm; Antigens; Antirheumatic Agents; Arthritis; Autoimmune Diseases; Autoimmunity; Biological Markers; Biology; Biometry; Blood; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CTLA4 gene; Cells; Clinical; Collection; Combined Modality Therapy; Complex; Data; Development; Disease; Doctor of Philosophy; Dose; Epidemiology; Equilibrium; Event; Fellowship; Genomics; Goals; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immunobiology; Immunogenomics; Immunologics; Immunology; Inflammation; Inflammatory Arthritis; Malignant Neoplasms; Mentors; Mentorship; Methods; Molecular; Oncology; PPBP gene; Pathogenesis; Patients; Physicians; Plant Roots; Play; Prednisone; Principal Investigator; Psoriatic Arthritis; Regulatory T-Lymphocyte; Research; Research Personnel; Research Training; Resistance; Rheumatoid Arthritis; Rheumatology; Role; Sampling; Scientist; Specificity; Steroid Resistance; Steroids; Synovial Fluid; T-Lymphocyte; Technology; Th1 Cells; Therapeutic; Training; Training Programs; Tumor Immunity; Universities; Work; autoimmune arthritis; base; biomarker-driven; bone erosion; cancer genomics; cancer immunotherapy; cancer therapy; career; career development; checkpoint therapy; cohort; experience; functional genomics; immune-related adverse events; in vivo; inhibitor; inhibitor therapy; innovation; insight; mouse model; optimal treatments; peripheral blood; preservation; programmed cell death protein 1; success; tool; treatment strategy; tumor; tumor immunology

PROJECT SUMMARY/ABSTRACT This proposal describes a rigorous training program for the career development of Dr. Sang Kim as an independent physician-scientist. The principal investigator is a physician-scientist who completed his PhD in immunobiology and his clinical rheumatology fellowship at Yale University. His career goal is to become an independent investigator studying rheumatic complications induced by immune-based cancer therapeutics. He proposes to expand his training in T cell and cancer immunology through an intensive training research experience under the mentorship of Dr. Roza Nurieva, a world leader with unparalleled intellectual and technical insight into the role of T cells in cancers and autoimmune diseases. In addition, because interactions of tumors and the host immune system are critical in development of immune-related adverse events (irAEs) induced by cancer immunotherapy, and because cutting-edge genomic technologies are a powerful tool in understanding the complex biology of the immune system, Dr. Kim will also have an opportunity to study cancer/functional genomics under the mentorship of Dr. Andrew Futreal (co-primary mentor), a world-renowned scientist in cancer genomics. The research objective of this proposal is to investigate mechanisms of arthritis associated with immune checkpoint inhibitor therapy (arthritis-irAE). Preliminary data for this proposal revealed the predominance of Th1 cell signatures in the patients with arthritis-irAE. In addition, Th17 cells were expanded in arthritis associated with combined PD-1 and CTLA-4 inhibitor therapy with steroid resistance. Furthermore, Dr. Kim observed that more CD4+ T cells were polarized into Th17 cells in skewing conditions in the presence of combined PD-1 and CTLA-4 inhibitors than in the presence of PD-1 inhibitor alone. From these results, Dr. Kim hypothesizes that Th1 cells play a critical role in the pathogenesis of arthritis-irAE and that Th17 cells are pivotal in steroid-resistant arthritis-irAE induced by combined PD-1 and CTLA-4 inhibitors. To address the hypothesis, Dr. Kim will investigate mechanisms leading to development of arthritis-irAE, with special focus on Th1/Tc1, Th17/Tc17, and regulatory T cells, and determine mechanism-driven biomarkers to predict development of arthritis-irAE, reflect arthritis disease activity, and predict steroid resistance. This proposal serves as a training vehicle for Dr. Sang Kim to become an expert in rheumatic complications induced by immune-based cancer therapy, an explosively emerging and challenging clinical entity in rheumatology.

项目概要/摘要 该提案描述了 Sang Kim 博士职业发展的严格培训计划 独立医师科学家。 主要研究者是一位医学科学家，完成了免疫生物学博士学位和临床研究 耶鲁大学风湿病学奖学金。他的职业目标是成为一名独立调查员 基于免疫的癌症治疗引起的风湿并发症。他建议扩大培训范围 在 Dr. T 细胞和癌症免疫学的指导下，通过强化培训研究经验来学习 T 细胞和癌症免疫学。 Roza Nurieva，世界领先者，对 T 细胞在癌症中的作用拥有无与伦比的知识和技术洞察力 和自身免疫性疾病。此外，由于肿瘤和宿主免疫系统的相互作用至关重要 癌症免疫治疗引起的免疫相关不良事件 (irAE) 的发展，并且因为 尖端基因组技术是理解免疫复杂生物学的有力工具 Kim 博士还将有机会在 Dr. Kim 的指导下研究癌症/功能基因组学。 Andrew Futreal（联合首席导师），世界著名的癌症基因组学科学家。 本提案的研究目的是研究与免疫相关的关节炎机制 检查点抑制剂疗法（关节炎-irAE）。该提案的初步数据揭示了 Th1 的主导地位 关节炎-irAE 患者的细胞特征。此外，Th17 细胞在关节炎相关的细胞中扩增。 PD-1 和 CTLA-4 抑制剂联合治疗具有类固醇耐药性。此外，金博士观察到 在 PD-1 和 PD-1 组合存在的情况下，更多 CD4+ T 细胞在倾斜条件下极化为 Th17 细胞 CTLA-4 抑制剂的效果优于单独使用 PD-1 抑制剂时的效果。根据这些结果，金博士推测 Th1 细胞在关节炎-irAE 的发病机制中发挥着关键作用，而 Th17 细胞在类固醇耐药中发挥着关键作用 PD-1 和 CTLA-4 抑制剂联合诱导的关节炎-irAE。为了解决这个假设，金博士将 研究导致关节炎-irAE 发生的机制，特别关注 Th1/Tc1、Th17/Tc17 和 调节性 T 细胞，并确定机制驱动的生物标志物来预测关节炎-irAE 的发展，反映 关节炎疾病活动，并预测类固醇抵抗。 该提案可作为 Sang Kim 医生成为风湿并发症专家的培训工具 由基于免疫的癌症治疗引起，这是一个爆炸性新兴且具有挑战性的临床实体 风湿病学。